3-substituted estra-1,3,5(10),16-tetraene derivatives, methods for the production thereof, pharmaceutical preparations containing same, and use thereof for the production of medicaments

Patent metadata

Field	Value
Publication number	US-9512169-B2
Application number	US-201314414386-A
Country	US
Kind code	B2
Filing date	Jul 5, 2013
Priority date	Jul 10, 2012
Publication date	Dec 6, 2016
Grant date	Dec 6, 2016

Abstract

The invention relates to AKR1C3 inhibitors and to processes for their preparation, to their use for the treatment and/or prophylaxis of diseases and also to their use for preparing medicaments for the treatment and/or prophylaxis of diseases, in particular bleeding disorders and endometriosis.

First claim

The invention claimed is:

1. A compound of the formula (I)

in which
A represents pyridin-3-yl, pyrimidin-5-yl, pyrimidin-4-yl, pyrazin-2-yl, pyridazin-4-yl, pyridazin-3-yl, optionally mono- or disubstituted by fluorine, chlorine, nitrile, hydroxyl, carboxyl, trifluoromethyl, pentafluoroethyl, methoxy, ethoxy, trifluoromethoxy, —OCH 2 CF 3 , —SO 2 CH 3 , —SO 2 CH 2 CH 3 , —(C═O)CH 3 , C 1 -C 4 -Alkyl, —CH 2 OH, —C(CH 3 ) 2 OH, —CONH 2 , —(C═O)NHCH 3 , —(C═O)NHCH 2 CH 3 , —(C═O)N(CH 3 ) 2 , —SO 2 NH 2 , —SO 2 NHCH 3 , —SO 2 N(CH 3 ) 2 ,
R 1 represents —O—CR a R b —Y where
R a and R b independently of one another represent represent hydrogen, methyl, ethyl, propyl, isopropyl, phenyl, 4-fluorophenyl, 3-fluorophenyl, 2-fluorophenyl, CH 3 —O—CH 2 —,
—CH 2 CF 3 or
R a and R b together represent —(CH 2 ) n — where n=2, 3, 4 or 5 or
R a and R b together represent —CH 2 —O—CH 2 —, —CH 2 —NH—CH 2 —, —CH 2 —N(CH 3 )—CH 2 —, —CH 2 CH 2 —O—CH 2 CH 2 —, —CH 2 CH 2 —NH—CH 2 CH 2 —, —CH 2 CH 2 —N(CH 3 )—CH 2 CH 2 —

—O—CR C R d —CR e R f —Y where
R c , R d , R e R f represent hydrogen or
R e , R f represent hydrogen and R c , R d independently of one another represent methyl, ethyl or together represent —(CH 2 ) n — where n=2, 3, 4, 5 or together represent —CH 2 —O—CH 2 — or —CH 2 CH 2 —O—CH 2 CH 2 — or
R c , R d represent hydrogen and R e , R f independently of one another represent methyl, ethyl, CF 3 CH 2 — or together represent —(CH 2 )n- where n=2, 3, 4, 5, —CH 2 CH 2 —O—CH 2 CH 2 —, —CH 2 CH 2 —NH—CH 2 CH 2 —, —CH 2 CH 2 —N(CH 3 )—CH 2 CH 2 —, —CH 2 —O—CH 2 —, —CH 2 —NH—CH 2 —, —CH 2 —N(CH 3 )—CH 2 — or
R d , R e , R f represent hydrogen and R e represents methyl, ethyl, trifluoromethyl or
R c , R d , R f represent hydrogen and R e represents methyl, ethyl, trifluoromethyl, hydroxyl, methoxy, trifluoromethoxy or
R d , R f represent hydrogen and R c , R e independently of one another represent methyl, ethyl, trifluoromethyl,

—O—CH 2 CH 2 CH 2 —Y,
—O—CH 2 C(CH 3 ) 2 CH 2 —Y,
—O—CH 2 CH 2 C(CH 3 ) 2 —Y,
—O—CH 2 CH 2 CH(CH 3 )—Y,
—O—CH 2 —CH(OH)—CH 2 —Y
—OCH 2 CH 2 CH 2 CH 2 —Y,
—CH 2 —Y,
—CR g R h —CR i R j —Y where

R g , R h , R i , R j represent hydrogen or
R g , R h , R i represent hydrogen and R j represents methyl, ethyl, trifluoromethyl or
R i , R j represent hydrogen and R g , R h represent methyl or together represent —CH 2 —,
—CH 2 CH 2 —, —CH 2 CH 2 CH 2 — or
R g represents methyl and R h , R i , R j represent hydrogen,

—CH 2 CH 2 CH 2 —Y,
—CH 2 CH 2 C(CH 3 ) 2 —Y or
—CH 2 CH 2 CH 2 CH 2 —Y and

Y represents —CO 2 H, —OH, —(C═O)NH 2 , —(C═ 0 )NHC 1-4 -alkyl, —S(═O)CH 3
or a salt thereof.

2. The compounds of claim 1 , in which
A represents pyridin-3-yl, pyrimidin-5-yl, pyrimidin-4-yl, pyrazin-2-yl, pyridazin-4-yl, pyridazin-3-yl, optionally monosubstituted by fluorine, chlorine, nitrile, hydroxyl, carboxyl, trifluoromethyl, methoxy, ethoxy, trifluoromethoxy, —SO 2 CH 3 ,
—(C═O)CH 3 , C 1 -C 4 -alkyl,

R 1 represents —O—CR a R b —Y where
R a and R b independently of one another represent represent hydrogen, methyl, ethyl, propyl, isopropyl, phenyl, CH 3 —O—CH 2 —, CF 3 CH 2 —,
—O—CR e R d —CR e R f —Y where
R c , R d , R e R f represent hydrogen or
R c , R d represent hydrogen and R e , R f independently of one another represent methyl, ethyl, CF 3 CH 2 — or
R d , R e , R f represent hydrogen and R c represents methyl, ethyl or
R c , R d , R f represent hydrogen and R e represents methyl, ethyl,
—O—CH 2 CH 2 CH 2 —Y,
—O—CH 2 C(CH 3 ) 2 CH 2 —Y,
—O—CH 2 CH 2 C(CH 3 ) 2 —Y,
—O—CH 2 CH 2 CH(CH 3 )—Y,
—O—CH 2 —CH(OH)—CH 2 —Y or
—CR g R h —CR i R j —Y where
R g , R h , R i , R j represent hydrogen or

R g , R h , R i represent hydrogen and R j represents methyl, ethyl or
R i , R j represent hydrogen and R g , R h represents methyl or
R g represents methyl and R h , R i , R j represent hydrogen and
Y represents —CO 2 H, —OH, —(C═O)NH 2 , —(C═O)NHC 1-4 -alkyl
or a salt thereof.

3. The compound of claim 1 , in which
A represents pyridin-3-yl, pyrimidin-5-yl, pyridazin-4-yl, optionally monosubstituted by fluorine, carboxyl, trifluoromethyl, methyl
R 1 represents —O—CR a R b —Y where
R a and R b represent hydrogen or R a represents hydrogen and R b represents methyl, ethyl, phenyl or CH 3 —O—CH 2 —
—O—CR c R d —CR e R f —Y where
R c , R d represent hydrogen and R e , R f represent methyl
—O—CH 2 CH 2 CH 2 —Y,
—O—CH 2 C(CH 3 ) 2 CH 2 —Y,
—O—CH 2 —CH(OH)—CH 2 —Y or

—CH 2 —CH 2 —Y and
Y represents —CO 2 H, —OH, —(C═O)NH 2 , —(C═O)NHC 1-4 -alkyl
or a salt thereof.

4. The compounds of formula (I) of claim 1 in which
A represents 5-fluoropyridin-3-yl, 5-(trifluoromethyl)pyridin-3-yl, 5-carboxypyridin-3-yl, 6-methylpyridin-3-yl, pyrimidin-5-yl, 6-methylpyridazin-4-yl and
R 1 represents —O—CR a R b —CO 2 H,
—O—CR a R b —(C═O)NH 2 ,
—O—CR a R b —(C═O)NHCH 2 CH 3 where
R a and R b represent hydrogen or
R a represents hydrogen and R b represents methyl, ethyl, phenyl, CH 3 OCH 2 —, —O—CR c R d —CR e R f —CO 2 H where
R c , R d represent hydrogen and R e , R f represent methyl,
—O—CH 2 CH 2 CH 2 —OH,
—O—CH 2 CH 2 CH 2 —CO 2 H,
—O—CH 2 C(CH 3 ) 2 CH 2 —OH or
—O—CH 2 —CH(OH)—CH 2 —OH

or a salt thereof.

5. The compound of claim 1 , wherein the compound is selected from the group consisting of
3-[17-(5-fluoropyridin-3-yl)estra-1,3,5(10),16-tetraen-3-yl]propanoic acid,
({17-[5-(trifluoromethyl)pyridin-3-yl]estra-1,3,5(10),16-tetraen-3-yl}oxy)acetic acid,
{[17-(5-fluoropyridin-3-yl)estra-1,3,5(10),16-tetraen-3-yl]oxy}acetic acid,
{[17-(6-methylpyridin-3-yl)estra-1,3,5(10),16-tetraen-3-yl]oxy}acetic acid,
{[17-(pyrimidin-5-yl)estra-1,3,5(10),16-tetraen-3-yl]oxy}acetic acid,
5-[3-(carboxymethoxy)estra-1,3,5(10),16-tetraen-17-yl]nicotinic acid,
{[17-(6-methylpyridazin-4-yl)estra-1,3,5(10),16-tetraen-3-yl]oxy}acetic acid,
3-{17-(5-fluoropyridin-3-yl)estra-1,3,5(10),16-tetraen-3-yl]oxy}-2,2-dimethylpropanoic acid,
4-{[17-(5-fluoropyridin-3-yl)estra-1,3,5(10),16-tetraen-3-yl]oxy}butanoic acid,
2-{[17-(5-fluoropyridin-3-yl)estra-1,3,5(10),16-tetraen-3-yl]oxy}propanoic acid,
2-{[17-(5-fluoropyridin-3-yl)estra-1,3,5(10),16-tetraen-3-yl]oxy}butanoic acid,
2-{[17-(5-fluoropyridin-3-yl)estra-1,3,5(10),16-tetraen-3-yl]oxy}-3-methoxypropanoic acid,
2-{[17-(3-pyridyl)estra-1,3,5(10),16-tetraen-3-yl]oxy}propanoic acid,
2-{[17-(5-fluoropyridin-3-yl)estra-1,3,5(10),16-tetraen-3-yl]oxy}propanamide,
3-{[17-(5-fluoropyridin-3-yl)estra-1,3,5(10),16-tetraen-3-yl]oxy}propan-1-ol,
3-{[17-(5-fluoropyridin-3-yl)estra-1,3,5(10),16-tetraen-3-yl]oxy}-2,2-dimethylpropan-1-ol,
3-{[17-(5-fluoropyridin-3-yl)estra-1,3,5(10),16-tetraen-3-yl]oxy}propan-1,2-diol, {[17-(5-fluoropyridin-3-yl)estra-1,3,5(10),16-tetraen-3-yl]oxy}(phenyl)acetic acid,
N-ethyl-2-({17-[5-(trifluoromethyl)pyridin-3-yl]estra-1,3,5(10),16-tetraen-3-yl}oxy)acetamide,
or a salt thereof.

6. A method of treatment of endometriosis, of uterine leiomyomas, of uterine bleeding disorders, of dysmenorrhoea, of prostate carcinoma, of prostate hyperplasia, of acne, of seborrhoea, of hair loss, of premature sexual maturity, of polycystic ovary syndrome, of breast cancer, of lung cancer, of endometrial carcinoma, of renal cell carcinoma, of bladder carcinoma, of non-Hodgkin lymphomas, of chronic obstructive pulmonary disease (COPD), of adiposity or of inflammatory pain comprising administering an effective amount of a compound of claim 1 to a human or animal in need thereof.

Assignees

• Bayer Pharma AG

Inventors

• Bothe Ulrich
• Busemann Matthias
• Fischer Oliver Martin
• Barak Naomi
• Rotgeri Andrea
• Marquardt Tobias
• Stegmann Christian

Classifications

• A61P5/28

  Antiandrogens · CPC title

• A61P7/04

  Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents · CPC title

• A61P5/32

  Antioestrogens · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P25/04

  Centrally acting analgesics, e.g. opioids · CPC title